7-Thiasubstituted-1,2,4-benzothiadiazine-1,1-dioxides and their salts

ABSTRACT

7-Mercapto(or alkyl- or aralkylthio)-1,2,4-benzothiadiazine-1,1dioxide compounds are described. Products are prepared by reducing a 7-chlorosulfonyl substituent to the 7-mercapto and then, if desired, alkylating or aralkylating to provide 7-thio substituent. Alternatively, a 4-RS-orthanilamide can be cyclized by known procedures to provide a 3-unsubstituted or 3-substituted analog. Products are xanthine oxidase inhibitors.

Novello Jul 1, 1975 [54] 7-THIASUBSTlTUTED-1,2,4- 3,419,552 12/1968 Whitehead et a1 260/243 D BENZOTHIADIAZINE-l ,l-DIOXIDES AND THEIR SALTS Primary Examiner-Nicholas S. Rizzo Attorney, Agent, or FirmDanie1 T. Szura; J. Jerome [75] Inventor: Frederick C. Novello, Berwyn, Pa. Behan [73] Assignee: Merck & Co., Inc., Rahway, NJ. [22 Filed: Mar. 20, 1972 [57] ABSTRACT 7-Mercapto(or alkylor ara1ky1thio)-1,2,4- [21] Appl' 236244 benzothiadiazine-l,l-dioxide compounds are described. Products are prepared by reducing a 7- [52] US. Cl. 260/243 D; 424/246 chlorosulfonyl substituent t0 the 7-mercapto and then, [51] Int. Cl C07d 93/32 if esired, alkylating or aralkylating to provide 7-thi0 [58] Field of Search 260/243 D stituen Alternatively, a 4-RS-orthani1amide can be cyclized by known procedures to provide a 3- [56] R f ren Cit d unsubstituted or 3-substituted analog. Products are UNITED STATES PATENTS 11/1967 de Stevens et a1. 260/243 D xanthine oxidase inhibitors.

7 Claims, No Drawings 7-THIASUBSTITUTED-l,2,4-BENZOTHIADIAZINE- 1,1-DIOXIDES AND THEIR SALTS This invention is concerned with benzothiadiazine compounds having a 7-mercapto or 7thio substituent as well as methods for their preparation. The novel products of this invention have been found to exhibit marked xanthine oxidase inhibiting properties equal to or greater than exhibited by allopurinol when evaluated in the same in vitro test.

The novel products of this invention have the struc tural formula:

and pharmacologically acceptable salts thereof wherein X represents halo (preferably chloro), C alkyl (particularly methyl) and trifluoromethyl; R represents hydrogen, a straight or branched chain lower alkyl having from I to 6 carbon atoms and phenyllower alkyl having from l to 3 carbon atoms (preferably benzyl); R represents hydrogen, lower alkyl having from 1 to 5 carbon atoms or substituted lower alkyl wherein the substituent is mono or dihalo (preferably chloro), and phenyl, the group CO lower alkyl having from 1 to 5 carbon atoms, an azine optionally substituted with one or more lower alkyl having 1 to 3 carbon atoms or a diazine optionally substituted with one or more lower alkyl having from I to 3 carbon atoms, or the group COl\lR R wherein R and R can be similar or dissimilar and selected from hydrogen, lower alkyl having 1 to 5 carbon atoms or hydroxy substituted lower alkyl having 1 to 5 carbon atoms.

The products of this invention can be prepared by a variety of known procedures. The methods illustrated below are representative of those employed in the preparation of the products specifically described herein:

When R in structure I is hydrogen, the products can readily be prepared by reduction of the 7-chloro sulfonyl substituent of the benzothiadiazine, A. Reduction advantageously is effected with slight warming of compound A with a mixture of stannous chloride and hydrochloric acid, zinc amalgam and sulfuric acid, zinc dust and sulfuric acid or tin and hydrochloric acid. Alkylation of the 7-mercapto product, la. provides product lb where R is other than hydrogen.

Slight heating of either product Ia or lb in the presence of base provides the orthanilamide, B, which can be used to prepare compounds of this invention which are wither unsubstituted in the 3-position or where certain specific substituents are desired in this position.

The appropriate orthanilamide derivative, B. can be reacted with an acid halide which. for practical purposes can be the acid chloride, followed by treatment with an organic base to provide product lc wherein R is other than hydrogen or a haloalkyl substituent. la the latter instance reaction with the haloalkanoic acid halide is followed by treatment with a salt of a weak acid and strong base. suitably sodium or potassium acetate or potassium fluoride.

When an organic base is employed following the reaction of the orthanilamide and acid chloride the base of choice is ammonia or a primary, secondary or tertiary amine particularly lower alkylor hydroxy substituted lower alkyl-amines. Employment of a tertiary amine in alcoholic solution provides the 3-carboxylic acid ester derivative whereas a primary or secondary amine gives the corresponding substituted amide. The 3-carbamoyl substituent is prepared employing ammonia following reaction of the orthanilamide with an alkoxalyl halide. Ammonia employed following reaction with a mono-carboxylic acid halide provides product where R is alkyl, phenalkyl, phenyl, an azine or diazine substituent. The nature of the alkyl and halo substituents in the alkoxalyl halide is not critical and can be any lower alkyl or halide and suitable, for practical purposes, ethyl oxalyl chloride can be employed.

X N 1. X N l l Reduction clso am as nar A Ia base. Alkylation L x 213 x TR base RS SO NH (R =II) RS '.lH

2 2 S0 B Ib R Acid Halide Fomic Acid etc.

x I R X T-Ii RS RS ,l-IH

is Id The R-acid chloride can be preformed and employed in the reaction or it can be prepared in situ by the addition of phosphorus oxychloride to a mixture of the orthanilamide and the R-carboxylic acid. When the acid chloride is preformed, the reaction advantagcously is conducted in the presence of an inert solvent such as dioxane, tetrahydrofuran, benzene, toluene, and the like and is facilitated by heating up to the reflux temperature of the reaction mixture. When the acid chloride is formed in situ, the phosphorus oxychloride serves not only to form the acid chloride but as solvent well.

The intermediate orthanilamide, B, additionally can be cyclized by known procedures to form product 1d, advantageously by heating with formic acid or an alkyl orthoformate.

The novel products of this invention are effective'inhibitors of xanthine oxidase, in decreasing the concentration of uric acid in the blood and urine and increasing the excretion of hypoxanthine and xanthine. The products are therefore useful in the treatment and management of gout preferably by oral administration of from 100 to 800 mg. per day in divided doses as prescribed by the physician.

The following examples describe various methods by which the products of this invention are prepared. It is to be understood that these examples are illustrative and not [imitative of the methods or products falling within the scope of this invention.

EXAMPLE 1 6-Chloro-7- mercapto-l ,2,4-benzothiadiazine- 1 l dioxide A solution of stannous chloride dihydrate (180.5 g., 0.80 mole) in concentrated hydrochloric acid (160 ml.) is added to a stirred solution of 6-chloro-7- chlorosulfonyLl ,2,4-benzothiadiazine-l ,l-dioxide (50.4 g, 0.16 mole) at 75C. and maintained at this temperature for an additional -30 minutes. The solution is concentrated in vacuo to one-tenth its original volume and poured into 8 liters of ice water containing concentrated hydrochloric acid (200 ml.). The solid formed is collected and added with stirring to one liter of saturated sodium bicarbonate solution. After 1 hour, the solution is filtered and the filtrate acidified with hydrochloric acid, the product collected on a filter, washed with water and recrystallized from ethanol providing product melting at 270-272C.

Analysis calculated for C H ClN O S C, 33.80; H, 2.03; N, 11.26. Found: C, 34.24; H, 2.14; N, 11.26.

By replacing the stannous chloride and concentrated hydrochloric acid employed in the above example by zinc amalgam and sulfuric acid, zinc dust and sulfuric acid, or tin and concentrated hydrochloric acid the same product is obtained.

EXAMPLE 2 6-Trifluoromethyl-7-mercapto- 1,2,4-benzothiadiazinel l -dioxide Step A: Preparation of 6Trifluoromethyl-7 chlorosulfonyl-l ,2,4-benzothiadiazine-l l -dioxide 6-Trifluoromethyl-7-sulfamoyll ,2,4-benzothiadiazine-1,1-dioxide (0.2 mole) is added portionwise with. stirring to chlorosulfonic acid (300 ml.) cooled in an ice-bath over minutes. The mixture is then heated for two hours on the steam bath, cooled and poured EXAMPLE 3 6-Methyl-7-mercapto-l ,2,4-benzothiadiazine- -l,1-dioxide .By replacing the -trifluoromethyl-7-sulfamoyll,2-,4-benzothiadiazinel ,1dioxide employed in Step A of Example 2 by an equivalent quantity of 6-methyl-7- sulfamoyl- 1 ,2,4-benzothiadiazinel 1 -dioxide and then following substantially the same procedure described in Steps 'A and B of Example 2, there is obtained 6- methyl-7-mercapto-l ,2,4-benzothiadizinel l -dioxide.

EXAMPLE 4 6-Chloro-7-isopropylthio-1,2,4-benzothiadiazinel l-dioxide A suspension of 6-chloro-7-mercaptol ,2,4- benzothiadiazine-l,l-dioxide (49.7 g., 0.02 mole), prepared as described in Example 1, in dimethylformamide (300 ml.) is heated with anhydrous potassium carbonate (27.6 g., 0.02 mole) with stirring. A solution results within 30 minutes whereupon isopropyl chloride (0.022 mole) is added with stirring over a 30-minute period. The reaction mixture is heated on a steam bath for one hour, poured onto a mixture of ice (2 liters) and water (2 liters) and acidified with concentrated hydrochloric acid. The solid is collected, stirred with 5% sodium hydroxide solution 1500 ml.) at room temperature and filtered. The filtrate is acidified with concen- EXAMPLE 5 6Chloro-7-benzylthiol ,2,4-benzothiadiazinel l dioxide, m.p. 26827lC.

Analysis calculated for C H ClN O S C, 49.62; H, 3.27; N, 8.27. Found: C, 50.14". H, 3.43: N, 8.24.

EXAMPLE 6 6-Chloro-7-n-propylthio-l .2,4-benzothiadiazinel ,ldioxide, m.p. 193-194C.

Analysis calculated for c H ClN O s- C, 41.30; H, 3.81; N, 9.64. Found: C, 41.55; H, 3.87; N, 9.72.

EXAMPLE 7 dioxide (prepared as described in Example 7) and following substantially the'samc procedure described in -ethylpropylthio)-l,2;4-benzothiadiazine-1,l-dioxide, Step there obfflined t mp S ethylpropylthlo)-5-chloroanlllne. m.p. 1 18 120 C.

Analysis calculated for C H, -,ClN O S- IC,45.2O;H, 4 Analysis calculated or CnHHCINZOQS c, 42.78; H, 4.74; N, 8.79. Found: c. 45.32; H, 4.54; N, 8.83. 555591.907. :-C.-4;.58; H. 5.4l; N. 9.09.

The products identified in Table l are prepared by In like manner the followmg comp ounds of Step the process of Example 4 employing equivalent quanti- S 9 Prepared y Yephlclhg the hehzoth'lilties of the benzothiadiazine and the alkyl chloride dlazme detlvatlve oy In p M by t q (R-Cl) identified in the table. lent quantity of a W) RC1 Ex. 4 i

HS SOEN RSVSOEN Ex. No. X R 1 70 6-triflu oromethyl-7-isopropylthio-1,2,4-benzo- 8 v CF (CH CH thiadiazine-l,l-dioxide (Ex. 8 product) 9 Z: 6-methyl-7-isopropylthio-1,2,4-benzothiadiazine- 1 CF?! CH-I(CHZE)ZZ I v 1,1-dioxide (Ex. 9 product) i i i; o-tr ifluoromethyl-7-n-propylthio-1.2.4-benzothiadia- 2lne-l,1-'dlo'xlde'(Ex. 10 product) 2 EXAMPLE l3 ..6imethyl-7 n-propylthio-1.2,4-benzothiadiazine-l.1- I dloxlde (Ex. 11 product) 3-(Py -y )-6-C lOrO-7-lsopropylthlo-- 6methyl-7-(1-ethylpropylthio)-l.2.;4-benzothiadia- 1,2,4-benzothiadiazine-l .l-dioxlde zihe l,l dioxide (EX 12 produc't) Step A-l: Preparation of 2-sulfamoyl-4-isopropylthiofonfwing SUhSwhfiaUX the Same Procedure 5 chloroaniline scribed ln Step A-l, pro vldlng respectively:

' 6-Chloro-7-isopropylthio-l,2,4-benzothiadiazine- 1,1-dioxide (0.03 mole), prepared as described in Ex ample 4, is dissolved in 10% aqueous sodiu'm'hydroxide Step A-S: Z-Sulfamoyl-4-isopropylthin-5- [50 ml and heated on the steam bath for one hour I T Step A-6: Z-sullamoyll-isopropylthio i The solution 15 chllled. acldlfied wlth hydrochlorlc acld mcthyltuiiline.

and the product upon recrystallization from a mixture 7 step Of ethanol and water melts at 137 -1 38C. Step A48: 2-sulfamoylA-mpropylthio-S- I Analysis calculated for C H ClN O S C, 38.50; H; t I Step AA):

4.66; N, 9.98. Found: C, 38.71; H, 4.60; N, 9.81. 40 th hi .5

Step A-2: Preparation of 2-sulfamoyl-4-n-propylthio-5- mcthyhnihncchloroaniline I; i i

By replacing the 1,2,4-benzothiadiazine derivative Step 8: Preparation of 3-(pyrid-4-yl)-6-chloro-7- employed in Step A-l by an equivalent quantity of 6- isopropylthio-l,2,4-benzothiadiazine-l ,l-dioxide h' -i' V An intimate mixture of the orthanilamide derivative f prepard as descnbed m Example a l prepared as described in Step A-1 (0.01 mole) and 4- lowlng substantlally the same procedure descrlbed ln pyridine carboxylic acid (001 mole) is heated with 20 p there is Obtained 2'sulfamoyl4n'propylthio' ml. of phosphorus oxychloride for 15 minutes at C. 5-Chl0r0ahihhei -P- 1090741100 and 45 minutes on the steam bath. The solution is An y Calculated for s la z Ct 3850; cooled;' poured onto ice and the product heated on the 4.66; N, 9.98. Found C, 38.14; H, 4.57; N, 9.83- steam bath with ethanol (50 ml.) and concentrated amp Preparation of 2-511]famoyl4'mercapto's monium hydroxide (50 ml.) for 2 hours. After concenchloroflnilin tration in vacuo, the residue is treated with 50 ml. of

By replacing the .2.4-benzothi i derivative water acidified with h drochloric acid yielding 3- employed in Step A-l by an equlvalent quantity of 6 4- 1 7 -13 4- chloro-7'mercaptolt2r4'benzothiadiazine'lthdioxidg benzothiadiazine-l.l-dioxide which following recrysahd following Substantially the Same Procedure tallization from a mixture of dimethylformamide and scribed in Step A-l there is obtained 2-sulfamoyl-4- water, melts at 254 256 C mercapt -5-chl0roani]ine, m.p. l92-195C. Analysis calculated for CI5HHCIN3O2S'EE 48.97; H,

Analysis calculated for ceHrClNtO-ts-i: C. 1 3.84; N. 11.42. Found: c, 49.14; H, 3.82; N. 1142.

Foundi C, 3.20; N, 11.74. The products identified in Table H are made By the A-4: Preparation of 2-sulfamoyl-4-( 1-ethylpropylthio)- process described in Example 13, Step B, except thfctt 5-chloroaniline ,the orthanilamide and the 4-pyridine carboxylic acid By replacing the 1,2,4-benzothiadiazine derivative are replaced by the orthanilamide and heterocyclic car; employed in Step A l by an equivalent quantity of 6- boxylic acid identified-iii the table. The R and R" chlo ogroups in the reactants are ietained unchanged in the 7-(1-ethy1propylthio)-l.2,4-benzothiadiazine-l,1- end product. l-c.

TABLE II C1 m Ex 13 c1 R" R"-COOH W RS 80 N11 RS /N A N A L Y S I S Calculated I Found 110. R R m.p.C Formula C H N C II N 14 i-pzopyl 225-26 C H C114 5 45.58 3.55 15.15 45.63 3.53 15.04

n-propyl N 284-86 C 14 (2114 0 3 48.97 3.84 11.42 48.54 3.53 11.13

16 n-propyl Q; 279-81 C 1-Z ClN 0 S 45.58 3.55 15.19 45.49 3.63 I 15.29

v 17 n-propyl N 248-50 C H ,C11 I O S 45.58 3.55 15.19 45.85 3.69 14.89

N 18 n-propyl 248-50 C 14 21N 0 S 47.05 3.95 14.63 47.05 3.95 14.62

N 19 n-propyl CH 254-56 c n cm o s 47.05 3.95 14.63 46.84 3.91 14.64

20 n-propyl 310-12 (2 11 C1N 0 S 45.58 3.55 15.19 45.51 3.46 15.02

Additional products l-c that are made by the procedure described in Example 13, Step B, by employing equivalent quantities of the orthanilamide and R"- COOH are identified in Table lll:

TABLE III X NH 2 R 'cooa RS so NH P Ex, No. X R R" v 4O Z 1 CF;, i-propyl I 22 -CH;, i-propyl N t I, 23 C F. n-propyl N 24 CH, n-propyl I 25 CF;. i-propyl N v l 26 CF:, |-prup \'l N EXAMPLE 27 3-Methyl-6-chloro-7-mercaptol ,2,4-benzothiadiazinel l -dioxide A mixture of 2-sulfamoyl-4-mercapto-5- chloroaniline, prepared as described in Example 13.

Step A-3 (0.02 mole) and acetyl chloride (0.022 mole) in ml. ofdioxane is heated under reflux for 24 hours. The solution is concentrated to dryness in vacuo and the residue dissolved in 75 ml. of ethanol and treated with 75 ml. of concentrated ammonium hydroxide in the cold. Thereafter'the solution is heated under reflux for three hours and concentrated to dryness in vacuo. The residue is suspended in ml. of water acidified with hydrochloric acid and the product, following recrystallization from dim'ethylformamide-water, melts at 304305 C. i I

Analysis calculated for CgHq-ClNzOgS: C, 36.57; H, 2.69; N. 10.66. Found: C, 36.98; H, 2.73; N, 10.61.

EXAMPLE 28 3-Ethoxycarbonyl-6-trifluoromethyl-7-isopropylthio- 1,2.4-benzothiadiazinel l -dioxide This product is prepared by replacing the orthanilamide, the acetyl chloride and the ammonium hydroxide employed in Example 27 by equivalent quantities of 2- sulfamoyl-4-isopropylthio-5-trifluoromethylaniline. ethyl oxalyl chloride and trimethylamine. respectively and otherwise following substantially the same procedure described in Example 27.

The products identified in Table IV are prepared following substantially the same procedure described in Example 27 but replacing the orthanilamide derivative, the acid chloride, and ammonium hydroxide by the reactants and reagents identified in the following table:

TABLE IV No. R base m.p."C

29 H C 1-l CH 111-1 011 I 300 30 i-propyl C H O C (CH N 258-60 31 i-propyl (CH NOC- ((1-1 N 212-14 C CH NH 323-25 CH HNOC- 3 32 i-propyl 3 33 n-propyl HO(CH HNOC- 111-1 ((11 H 277-79 plus dioxane Formula A N A L 1! S I Calculated Found EXAMPLE 34 3-Carbarnoyl-6-chloro-7-isopropylthio-l ,2,4- benzothiadiazinel l-dioxide A mixture of 2-sulfamoyl-4-isopropylthio-5- chloroaniline (0.02 mole) and ethyl oxalyl chloride (0.022 mole) in dioxane (40 ml.) is heated under reflux for 18 hours and then concentrated to dryness in vacuo. The residue is dissolved in a mixture of ethanol (30 ml.) and concentrated ammonium hydroxide (30 ml.) and stirred at room temperature for 2-3 days. The solution is concentrated to dryness in vacuo and the residue stirred in sodium bicarbonate solution and filtered. The filtrate is acidified and the product recrystallized from dimethylformamide-water providing 3- carbamoyl-6-chloro-7-isopropylthio-1,2,4- benzothiadiazine-l,l-dioxide, m.p. 279280 C.

Analysis calculated for C H CIN O S C, 39.58; H, 3.62; N, 12.59. Found: C, 39.41; H, 3.77; N, 12.62.

EXAMPLE 35 3-Carbamoyl-6-chloro-7-( l-ethylpropylthio)-1,2,4- benzothiadiazine-l l -dioxide By replacing the orthanilamide employed in Example 34 by an equimolecular quantity of 2-sulfamoyl-4-(1- ethylpropylthio)-5-chloroaniline and following substantially the same procedure described in Example 34 there is obtained 3-carbamoyl-6-chloro-7-( lethylpropylthio)-1,2,4-benzothiadiazine-l ,l-dioxide, m.p. 287-289 C.

Analysis calculated for c,;l-i,,,c1N,o s,; C, 43.15; H, 4.46; N, 11.61. Found: C, 43.18; H, 4.38; N, 11.63.

EXAMPLE 36 3-Chloromethyl-6-chloro-7-isopropylthiol ,2,4- benzothiadiazine-l l -dioxide A mixture of 2-sulfamoyl-4-isopropylthio-S- chloroaniline (0.02 mole) and chloroacetyl chloride (0.022 mole) in dioxane (75 ml.) is heated under reflux for 24 hours. The solution then is concentrated to dryness in vacuo. the residue dissolved in ethanol (60 ml.) and heated under reflux with potassium acetate (0.022 mole) and water ml.) for 2 hours. The alcohol is removed in vacuo and the solution then acidified with hydrochloric acid. The precipitated product is recrystallized from a mixture of methanol and water to provide 3-chloromethyl-6-chloro-7-isopropylthio-1,2,4- benzothiadiazine-l,l-dioxide, m.p. 248250 C.

Analysis calculated for C,,H,- Cl N O S- C, 38.94; H. 3.57; N, 8.26. Found: C. 39.16; H, 3.65; N, 8.28.

EXAMPLE 37 3-Chloromethyl6-trifluoromethyl-7-isopropylthiol,2,4-benzothiadiazinel 1 -dioxide This product is prepared following substantially the same procedure described in Example 36 with the ex ception that an equivalent quantity of 2-sulfamoyl-4- isopropylthio-S-trifluoromethylaniline is employed in place of the aniline reactant used in Example 36.

EXAMPLE 38 3-Chloromethyl-6-chloro-7-( l-ethylpropylthio )-l ,2,4-

' benzothiadiazinel l -dioxide EXAMPLE 39 3-Chloromethyl-6-methyl-7-( 1-ethy1propylthio)- 1 ,2,4- benzothiadiazine-l l dioxide This product is prepared following substantially the same procedure described in Example 36 except that an equivalent quantity of 2-sulfamoyl-4-(1- ethylpropylthio)-5-methylaniline is substituted for the aniline reactant employed in Example 36.

EXAMPLE 40 3-Dichloromethyl-6-chl0ro-7-isopropylthio-l ,2,4- benzothiadiazine-l 1 -dioxide By replacing the acid chloride employed in Example 36 by an equimolecular quantity of dichloroacetyl chloride and following substantially the same proce dure described in Example 36 there is obtained 3- 5. A product as claimed in claim 1 wherein X is trifluoromethyl and R is pyridyl.

4. A product as claimed in claim 1 wherein chloro.

5. A product as claimed in claim 1 wherein chloro and R is pyridyl.

'6'. A product claimed in claim 1 wherein chloro, R is isopropyl and R is 4-pyridyl.

7. A product as claimed in claim 1 wherein chloro. R is n-propyl and R is 4-pyridyl. 

1. 3-R1-6-X-7-RS- 1,2,4-BENZOTHIADIAZINE-1, 1 -DIOXIDES AND PHARMACOLOGICALLY ACCEPTABLE SALTS THEREOF WHEREIN X REPRESENTS C1-3 ALKYL, CHLORO AND TRIFLUOROMETHYL, R1 REPRESENTS PYRIDYL AND C1-C3-ALKYL SUBSTITUTED PYRIDYL AND R REPRESENTS HYDROGEN, C1-C6 LOWER ALKYL AND PHENYL-C1-C3-ALKYL.
 2. A product as claimed in claim 1 wherein X is trifluoromethyl.
 3. A product as claimed in claim 1 wherein X is trifluoromethyl and R1 is pyridyl.
 4. A product as claimed in claim 1 wherein X is chloro.
 5. A product as claimed in claim 1 wherein X is chloro and R1 is pyridyl.
 6. A product as claimed in claim 1 wherein X is chloro, R is isopropyl and R1 is 4-pyridyl.
 7. A product as claimed in claim 1 wherein X is chloro, R is n-propyl and R1 is 4-pyridyl. 